New evidence supporting female protective effect in patients with congenital anomalies and neurodevelopmental disorders

Abstract

The influence of chromosomal sex on human diseases is recognized but underresearched, particularly in diseases with early developmental origins. Copy number variations (CNVs) from sex chromosomes or autosomes, which cause different gene expressions, may influence the disease preferences in females and males. Chromosomal microarray is a standard method for detecting CNVs, with a diagnostic yield of approximately 15 % among patients with congenital anomalies and neurodevelopmental disorders, the primary indications for the analysis. Here, we explore sex disparities in phenotype prevalence and CNV detection rates in patients referred for chromosomal microarray to identify sex-biased traits and CNVs. Our cohort comprises 1412 patients, with a male-to-female ratio of 1.6 to 1. Despite being outnumbered, females are significantly more likely to receive a genetic diagnosis through this type of molecular karyotyping. Most of the patients have neurodevelopmental disorders with other comorbidities. Females have a higher frequency of comorbidities, but the difference in diagnostic yield is significant only in the groups with simpler phenotypes (≤2 comorbidities). Higher diagnostic yield is revealed for congenital heart disease, urogenital anomalies, and the autism spectrum group. All three categories show populational preponderance in males, supporting a higher threshold liability model in females. © 2025 Elsevier B.V.